Plasmodial sugar transporters as anti-malarial drug targets and comparisons with other protozoa

Slavic, Ksenija; Krishna, Sanjeev; Derbyshire, Elvira T.; Staines, Henry M.

doi:10.1186/1475-2875-10-165

Cited by 43 publications

(29 citation statements)

References 67 publications

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“…PfHT hexose transporter function is known to be required for Plasmodium parasite development in culture and in animal models (14,18,19,25,35). We find that not only does lopinavir directly block glucose uptake into P. falcipa- 3 H]2DOG uptake was determined in the presence of various concentrations of lopinavir and substrate.…”

Section: Discussionmentioning

confidence: 80%

“…Similar to GLUT1 and GLUT4, the predicted topology of PfHT comprises 12 transmembrane helices, forming a central glucose permeation path. Key residues that are involved in glucose binding and transport are preserved between the human and malaria glucose transporters (14,15).…”

mentioning

confidence: 99%

“…Not surprisingly, infected erythrocytes show an ϳ100-fold increase in glucose consumption compared to uninfected erythrocytes (17). PfHT (PF3D7_0204700) is the principal glucose transporter, transcribed from a single-copy gene with no close paralogue (14). PfHT has been genetically validated as essential in Plasmodium parasites (18) and has been independently chemically validated as a novel drug target against malaria (14,19).…”

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confidence: 99%

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The Glucose Transporter PfHT1 Is an Antimalarial Target of the HIV Protease Inhibitor Lopinavir

Kraft

Armstrong

Heitmeier

et al. 2015

Antimicrob Agents Chemother

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Malaria and HIV infection are coendemic in a large portion of the world and remain a major cause of morbidity and mortality. Growing resistance of Plasmodium species to existing therapies has increased the need for new therapeutic approaches. The Plasmodium glucose transporter PfHT is known to be essential for parasite growth and survival. We have previously shown that HIV protease inhibitors (PIs) act as antagonists of mammalian glucose transporters. While the PI lopinavir is known to have antimalarial activity, the mechanism of action is unknown. We report here that lopinavir blocks glucose uptake into isolated malaria parasites at therapeutically relevant drug levels. Malaria parasites depend on a constant supply of glucose as their primary source of energy, and decreasing the available concentration of glucose leads to parasite death. We identified the malarial glucose transporter PfHT as a target for inhibition by lopinavir that leads to parasite death. This discovery provides a mechanistic basis for the antimalarial effect of lopinavir and provides a direct target for novel drug design with utility beyond the HIV-infected population.

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Section: Discussionmentioning

confidence: 80%

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confidence: 99%

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confidence: 99%

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The Glucose Transporter PfHT1 Is an Antimalarial Target of the HIV Protease Inhibitor Lopinavir

Kraft

Armstrong

Heitmeier

et al. 2015

Antimicrob Agents Chemother

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“…Additionally, three other putative sugar transporters have been identified in the genome of P. falciparum. However, they show \21% sequence identity compared with PfHT, and their function has not yet been investigated (48).…”

Section: P Falciparum Glucose Transportersmentioning

confidence: 99%

Glucose‐6‐phosphate metabolism in Plasmodium falciparum

2012

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Malaria is still one of the most threatening diseases worldwide. The high drug resistance rates of malarial parasites make its eradication difficult and furthermore necessitate the development of new antimalarial drugs. Plasmodium falciparum is responsible for severe malaria and therefore of special interest with regard to drug development. Plasmodium parasites are highly dependent on glucose and very sensitive to oxidative stress; two observations that drew interest to the pentose phosphate pathway (PPP) with its key enzyme glucose‐6‐phosphate dehydrogenase (G6PD). A central position of the PPP for malaria parasites is supported by the fact that human G6PD deficiency protects to a certain degree from malaria infections. Plasmodium parasites and the human host possess a complete PPP, both of which seem to be important for the parasites. Interestingly, there are major differences between parasite and human G6PD, making the enzyme of Plasmodium a promising target for antimalarial drug design. This review gives an overview of the current state of research on glucose‐6‐phosphate metabolism in P. falciparum and its impact on malaria infections. Moreover, the unique characteristics of the enzyme G6PD in P. falciparum are discussed, upon which its current status as promising target for drug development is based. © 2012 IUBMB IUBMB Life, 64(7): 603–611, 2012

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“…Among all these candidates, PfHT1 is the only malarial transporter that has been validated both chemically and genetically (Staines et al, 2010). Gene deletion studies and D-glucose derivatives used as inhibitors confirmed the essential role of the hexose transporters for the asexual parasite development and other parasite stages (Blume et al, 2010, Slavic et al, 2011.…”

Section: Transportersmentioning

confidence: 99%